Table 2.
Overview of published hepatotoxicity screens in organotypic 3D models. Only studies in which ≥10 compounds were analyzed, are listed.
| Culture paradigm | Cell system | Number of compounds tested (DILI positive/DILI negative | Toxicity threshold | Exposure time | Results/conclusions | Reference |
|---|---|---|---|---|---|---|
| Scaffold-free spheroid | HepaRG | 12 (10/2) | 30x cmax | 24 h/7 days single exposure | 24 h exposure: 6 out of 10 are predicted correctly for hepatotoxins compared to 5 out of 10 in 2D HepaRG culture; 7 day exposure: 7 out of 10 are predicted correctly for hepatotoxins compared to 6 out of 10 in 2D HepaRG culture. | (Ott et al., 2017) |
| Scaffold-free spheroid | HepaRG | 10 (6/4) | No threshold defined | 24 h single exposure/6 days repeated exposure | Repeated exposure for 3D HepaRG spheroid shows higher sensitivity than 24 h single exposure for 3D HepaRG spheroid, 2D HepaRG, and PHH | (Ramaiahgari et al., 2017) |
| Scaffold-free spheroid | hiPSC-derived HLC | 24 (20/4) | No threshold defined | 24 h single exposure | HLC spheroid is more sensitive than HepG2 spheroid. However, for acetaminophen and troglitazone, PHH monolayer culture performs better than HLC spheroid | (Takayama et al., 2013) |
| Scaffold-free spheroid | hiPSC-derived HLC | 48 (42/6) | No threshold defined | 72 h single exposure | 36 out of 42 hepatotoxins elicit detectable toxicity effects. However, 12 anticancer drugs that are generally cytotoxic are also included as DILI positive compounds | (Sirenko et al., 2016) |
| Scaffold-free spheroid | PHH | 110 (69/41) | 25x and 100x cmax | 14 days repeated exposure | 47.8% sensitivity and 92.7% specificity at 25x Cmax; 59.4% sensitivity and 80.5% specificity at 100x margin of safety | (Proctor et al., 2017) |
| Scaffold-free spheroid | PHH | 123 (70/53) | 1x, 5x, and 20x cmax | 14 days repeated exposure | 69% sensitivity and 100% specificity at 20x Cmax exposure concentration using 80% cell viability as threshold | (Vorrink et al., 2018) |
| Scaffold-based spheroid | HepG2 | 12 (8/4) | No threshold defined | 24 h single exposure/6 days repeated exposure | Repeated exposure for 3D HepG2 spheroid shows higher sensitivity than 24 h single exposure for 3D HepG2 spheroid and 2D HepG2 | (Ramaiahgari et al., 2014) |
| Scaffold-based spheroid | HepaRG | 19 (14/5) | 100x cmax | 24 h single exposure/7 days repeated exposure | Liver biomatrix scaffold 3D HepaRG spheroid shows higher sensitivity than non-scaffold scaffold 3D HepaRG spheroid; repeated exposure shows higher sensitivity than 24 h single exposure | (Liu et al., 2018) |
| MPCC | PHH-fibroblast | 45 (35/10) | 100x cmax | 9 days repeated exposure | PHH-fibroblast: 65.7% sensitivity and 90% specificity. Predictions are based on multiple endpoints |
(Khetani et al., 2013) |
| MPCC | hiPSC-derived HLC-fibroblast | 47 (37/10) | 100x cmax | 6 days repeated exposure | 65% sensitivity and 100% specificity | (Ware et al., 2015) |
| Perfused liver chip | PHH-fibroblast | 19 (12/7) | 100x cmax | 24 h single exposure and 13 days repeated exposure | Human mono-culture: 50%. Human co-culture: 83%. |
(Novik et al., 2017) |